Does a Lack of Serotonin Really Affect Depression?

In the U.S., nearly 17 million of the population is affected by depression, mostly adults, and even this figure is underestimated as many cases are not even brought to medical attention. Depression is a mood disorder that results in sadness, loss of interest, irritable mood and cognitive changes that affect an individual’s ability to function. 

Many environmental and genetic factors lead to depression, but the exact cause is unknown. One common and persistent idea since the 1960s is that abnormalities in the brain chemicals, specifically serotonin, result in depression. But there isn’t much evidence to support this theory. So, it begs the question, does a lack of serotonin really affect depression?

What Is Serotonin?

Before diving into the relationship between serotonin and depression, let’s learn what serotonin is and how it helps the body.

Serotonin is a neurotransmitter that plays a fundamental physiological role in the human body. Neurotransmitters are nerve cells that carry chemical signals that travel through cells and encourage the body to react in a certain manner. They regulate multiple physiological functions, such as appetite, flight or fight response, or emotions. 

There are more than 100 neurotransmitters in the human body, including serotonin. Serotonin regulates multiple activities, such as stabilizing mood, sexual desire, behavior, digestion, etc. Because of these capabilities, serotonin is the primary treatment target for multiple psychological and neurological disorders, such as depression. 

Relationship Between Serotonin and Depression – How It All Started

The link between serotonin and depression was first established in the early 1960s. As a result, SSRI antidepressants were developed that are still widely used today and backed by leading researchers. But there is no concrete evidence available that can support this relationship.

The relationship between serotonin and depression was critical in the past because of how serotonin levels affect the body. For instance, high serotonin levels create the “serotonin syndrome” effect. Its symptoms include agitation, confusion, headache, nausea, vomiting, shivering and rapid heart rate. It happens when an individual accidentally mixes two or more medications. 

In contrast, low serotonin levels lead to serotonin deficiency and affect an individual’s mood and ability to function properly. Multiple factors can cause low serotonin levels, such as nutritional and vitamin deficiency, low tryptophan levels, etc. Researchers also believe that low serotonin levels are associated with anxiety, insomnia, weight gain and irritable bowel syndrome. 

Because of this, it is one of the most investigated neurotransmitters. According to a study conducted in 2017, convergent data from studies on cerebrospinal fluid levels of 5-hydroxyindolacetic acid, tryptophan depletion, peripheral models of presynaptic serotonergic neurons, like platelets, neuroendocrine challenges and autopsy seemed to support the presence of decreased functioning of the serotonin system in depression. However, if these findings are analyzed, you will also find negative results, but most were neglected. Thus, all these studies led to the advent of Selective Serotonin Reuptake Inhibitors (SSRI), which are the first line of medication for severe anxiety, depression and neuropsychiatric disorders and are still widely used today.

Treatment for Depression

SSRIs are used as the first line of pharmacotherapy for depression and other neuropsychiatric disorders due to their efficiency, safety and tolerability.[3] Common antidepressants include Fluoxetine, Sertraline, Fluvoxamine and Citalopram. SSRIs work by holding back the reuptake of serotonin, causing serotonin activity to increase. They have fewer effects on other neurotransmitters, unlike other classes of antidepressants, such as dopamine or norepinephrine.

SSRIs also have relatively fewer side effects, such as:

•     Headache
•     Agitation or mild irritability
•     Dyssomnia or sleepiness
•     Nausea or constipation
•     Dizziness
•     Sexual dysfunction

To prevent these side effects, the initial dose is sub-therapeutic and is prescribed for 1 to 2 weeks, which then gradually leads to the therapeutic dose.

According to recent research, there is no clear relationship between serotonin and depression, then why do SSRIs work? There must be an explanation. 

One thing is clear, SSRIs do work for individuals with depression but just not because of the reasons we thought.

Why Do SSRIs Work?

Let’s discuss their mechanism in more detail. Serotonin is a neurotransmitter that is released by a neuron and binds to another neuron. After traveling through cells and transmitting the signals, serotonin is taken back up to await when it is needed. SSRIs work by hindering this reuptake, causing the serotonin to stay afloat between the cells and relay its message multiple times before being taken up. If that’s the case, SSRIs simply increase serotonin levels. However, the authors of The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence suggest that in the long term, SSRIs might reduce serotonin levels in the brain.

So, how do they work? Many researchers believe that antidepressants work by changing other aspects of the brain chemistry aside from serotonin.

Since imipramine’s introduction in 1957, numerous antidepressants have been developed with increasing specificity for the monoamine systems, including selective serotonin, dopamine and norepinephrine agents. While these agents lead to an immediate change in monoaminergic neurotransmission, they typically require at least four weeks of treatment before leading to beneficial effects. Moreover, they are only effective around 30%-40% of the time. These observations have led to the conclusion that rather than treating a “serotonin deficit,” antidepressants may work by promoting some form of neuroplasticity in brain circuits that are relevant to depression.

Simply put, antidepressants work by increasing neuroplasticity, which is the ability of the brain to change neural networks after growth and reorganization or causing stress to have less harmful effects on neuroplasticity.

The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence

In 2022, an umbrella review was conducted on the serotonin system. An umbrella review surveys existing systematic reviews and meta-analyses relevant to a research question and represent one of the highest levels of evidence synthesis available.

The researchers first conducted a scoping review to identify areas of research consistently held to support the serotonin hypothesis of depression. The research identified six areas, and conclusions were made on serotonin and 5-HIAA, receptors, serotonin transporter (SERT), depletion studies and SERT gene and gene-stress interactions.

Areas of research that provided moderate or high certainty of the evidence, such as the studies of plasma serotonin and metabolites and the genetic and gene-stress interaction studies, all showed no association between markers of serotonin activity and depression. Some other areas suggested findings consistent with increased serotonin activity, but the evidence was of very low certainty, mainly due to small sample sizes and possible residual confounding by current or past antidepressant use.

To conclude, a review of the major areas of serotonin research shows that there is no link between depression and serotonin or if depression is caused by low serotonin activity.

A Parting Note 

Researchers have widely put forward the serotonin hypothesis and chemical imbalance theory for depression over the past few decades. This has led the general public to believe that depression is caused by serotonin and also influenced their decision whether to continue antidepressant medication or not, leading to a lifelong dependency on these drugs. Low serotonin levels might affect your body in some ways, but it has shown no strong link with depression.